The comparison of the immunological state of pregnancy to an immunosuppressed host-graft model continues to lead research and clinical practice to ill-defined approaches. This Review discusses recent evidence that supports the idea that immunological responses at the receptive maternal-fetal interface are not simply suppressed but are instead highly dynamic. We discuss the crucial role of trophoblast cells in shaping not only the way in which immune cells respond to the invading blastocyst but also how they collectively react to external stimuli. We also discuss the role of the microbiota in promoting a tolerogenic maternal immune system and highlight how subclinical viral infections can disrupt this status quo, leading to pregnancy complications.

The unique immunological and microbial aspects of pregnancy

The signals and mechanisms that synchronize the timing of human parturition remain a mystery and a better understanding of these processes is essential to avert adverse pregnancy outcomes. Although our insights into human labor initiation have been informed by studies in animal models, the timing of parturition relative to fetal maturation varies among viviparous species, indicative of phylogenetically different clocks and alarms; but what is clear is that important common pathways must converge to control the birth process. For example, in all species, parturition involves the transition of the myometrium from a relaxed to a highly excitable state, where the muscle rhythmically and forcefully contracts, softening the cervical extracellular matrix to allow distensibility and dilatation and thus a shearing of the fetal membranes to facilitate their rupture. We review a number of theories promulgated to explain how a variety of different timing mechanisms, including fetal membrane cell senescence, circadian endocrine clocks, and inflammatory and mechanical factors, are coordinated as initiators and effectors of parturition. Many of these factors have been independently described with a focus on specific tissue compartments.In this review, we put forth the core hypothesis that fetal membrane (amnion and chorion) senescence is the initiator of a coordinated, redundant signal cascade leading to parturition. Whether modified by oxidative stress or other factors, this process constitutes a counting device, i.e. a clock, that measures maturation of the fetal organ systems and the production of hormones and other soluble mediators (including alarmins) and that promotes inflammation and orchestrates an immune cascade to propagate signals across different uterine compartments. This mechanism in turn sensitizes decidual responsiveness and eventually promotes functional progesterone withdrawal in the myometrium, leading to increased myometrial cell contraction and the triggering of parturition. Linkage of these processes allows convergence and integration of the gestational clocks and alarms, prompting a timely and safe birth. In summary, we provide a comprehensive synthesis of the mediators that contribute to the timing of human labor. Integrating these concepts will provide a better understanding of human parturition and ultimately improve pregnancy outcomes.

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Novel concepts on pregnancy clocks and alarms: redundancy and synergy in human parturition

Inflammation is essential for successful embryo implantation, pregnancy maintenance and delivery. In the last decade, important advances have been made in regard to endogenous, and therefore non-infectious, initiators of inflammation, which can act through the same receptors as pathogens. These molecules are referred to as damage-associated molecular patterns (DAMPs), and their involvement in reproduction has only recently been unraveled. Even though inflammation is necessary for successful reproduction, untimely activation of inflammatory processes can have devastating effect on pregnancy outcomes. Many DAMPs, such as uric acid, high-mobility group box 1 (HMGB1), interleukin (IL)-1 and cell-free fetal DNA, have been associated with pregnancy complications, such as miscarriages, preeclampsia and preterm birth in preclinical models and in humans. However, the specific contribution of alarmins to these conditions is still under debate, as currently there is lack of information on their mechanism of action. In this review, we discuss the role of sterile inflammation in reproduction, including early implantation and pregnancy complications. Particularly, we focus on major alarmins vastly implicated in numerous sterile inflammatory processes, such as uric acid, HMGB1, IL-1α and cell-free DNA (especially that of fetal origin) while giving an overview of the potential role of other candidate alarmins.

/pdf/sterile-inflammation-and-pregnancy-complications-a-review-3zcbmzwdvw.pdf

Sterile inflammation and pregnancy complications: a review.

Spontaneous preterm birth: advances toward the discovery of genetic predisposition

Antibiotic administration can eradicate intra-amniotic infection or intra-amniotic inflammation in a subset of patients with preterm labor and intact membranes

PROBLEM Sterile intra-amniotic inflammation is associated with spontaneous preterm labor. Alarmins are proposed to mediate this inflammatory process. The aim of this study was to determine whether intra-amniotic administration of an alarmin, HMGB1, could induce preterm labor/birth. METHOD OF STUDY Pregnant B6 mice were intra-amniotically or intraperitoneally injected with HMGB1 or PBS (control). Following injection, the gestational age and the rates of preterm birth and pup mortality were recorded. RESULTS Intra-amniotic injection of HMGB1 led to preterm labor/birth [HMGB1 57% (4/7) versus PBS 0% (0/6); P = 0.049) and a high rate of pup mortality at week 1 [HMGB1 60.9 ± 11.7% (25/41) versus PBS 28.9 ± 12.6% (11/38); P = 0.001). Intraperitoneal injection of HMGB1 did not induce preterm labor/birth. CONCLUSION Intra-amniotic administration of HMGB1 induces preterm labor/birth.

Tamara Roumayah

Papers

Intra-Amniotic Administration of HMGB1 Induces Spontaneous Preterm Labor and Birth.